Minoxidil (i.e., 2,4-diamino-6-piperidinyl-pyrimidine-3-oxide) is an active ingredient of Loniten (registered trademark) and Rogaine (registered trademark), and it is commercially available from Pharmacia and Upjohn for treatment of hypertension and for treatment and prevention of androgenic alopecia (male pattern baldness and female pattern baldness). A method for preparing minoxidil and use thereof for an antihypertensive agent are disclosed in U.S. Pat. No. 3,461,461. A method for use of the compound to grow hair and to treat male pattern baldness and female pattern baldness and a topical preparation therefor are disclosed in U.S. Pat. Nos. 4,139,619 and 4,596,812.
A pharmaceutical composition for topical application, such as Rogaine (registered trademark), can be in various forms, such as a solution, gel or suspension. When a composition for topical application is a solution or gel; i.e., when an active ingredient such as minoxidil is dissolved in a carrier solution, in general, absorption can be improved, as compared with a composition for topical application in the form of a suspension; i.e., a case where a composition comprising an active ingredient is suspended in the composition.
Minoxidil is poorly soluble in water. When it is dissolved in an aqueous solvent, 50% or more of the solution is generally composed of ethanol (e.g., JP Patent Publication (kokai) No. 2004-59587 A), and adverse effects resulting therefrom (e.g., stimulation of the scalp and deteriorated sense of use, such as stickiness, due to increased solvent amount) are issues of concern. JP Patent Publication (kokai) No. 2006-176447 A discloses a composition that yields reduced stimulation of the scalp caused by ethanol; however, the ethanol content is 40% or more and the problem of stimulation is not fundamentally resolved. Thus, improvement in solubility and absorption of minoxidil still depends on percutaneous absorption that is carried out in a concentration-gradient manner by elevating the concentration of minoxidil to be dissolved with the aid of an organic solvent. There was no means for improving absorption efficiency without the use of an organic solvent.
The term “bile acid” is a generic term for compounds that are steroid derivatives which are contained in bile generated and absorbed in vivo and have cholane skeleton. Bile acid is occasionally used as a solubilizer at the industrial level. Specifically, ursodeoxycholic acid is used as a choleretic drug, and deoxycholic acid is used as a dispersant for a pharmaceutical additive, although its remarkable effects for solubilizing minoxidil were not known in the past. Also, JP Patent Publication (kokai) No. H1-174355 A (1989) discloses that mixing of monoacylglycerophospholipid, fatty acid monoglyceride, and bile acid would double the percutaneous absorption efficiency of indomethacin. However, such doubling was not achieved solely by bile acid, and effects of accelerating percutaneous absorption by bile acid alone were not known.